Background:
Patients affected by different types of autoimmune diseases, including common conditions such as multiple sclerosis (MS) and rheumatoid arthritis (RA), are often treated with ...immunosuppressants to suppress disease activity. It is not fully understood how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific humoral and cellular immunity induced by infection and/or upon vaccination is affected by immunosuppressants.
Methods:
The dynamics of cellular immune reactivation upon vaccination of SARS-CoV-2 experienced MS patients treated with the humanized anti-CD20 monoclonal antibody ocrelizumab (OCR) and RA patients treated with methotrexate (MTX) monotherapy were analyzed at great depth via high-dimensional flow cytometry of whole blood samples upon vaccination with the SARS-CoV-2 mRNA-1273 (Moderna) vaccine. Longitudinal B and T cell immune responses were compared to SARS-CoV-2 experienced healthy controls (HCs) before and 7 days after the first and second vaccination.
Results:
OCR-treated MS patients exhibit a preserved recall response of CD8
+
T central memory cells following first vaccination compared to HCs and a similar CD4
+
circulating T follicular helper 1 and T helper 1 dynamics, whereas humoral and B cell responses were strongly impaired resulting in absence of SARS-CoV-2-specific humoral immunity. MTX treatment significantly delayed antibody levels and B reactivation following the first vaccination, including sustained inhibition of overall reactivation marker dynamics of the responding CD4
+
and CD8
+
T cells.
Conclusions:
Together, these findings indicate that SARS-CoV-2 experienced MS-OCR patients may still benefit from vaccination by inducing a broad CD8
+
T cell response which has been associated with milder disease outcome. The delayed vaccine-induced IgG kinetics in RA-MTX patients indicate an increased risk after the first vaccination, which might require additional shielding or alternative strategies such as treatment interruptions in vulnerable patients.
Funding:
This research project was supported by ZonMw (The Netherlands Organization for Health Research and Development, #10430072010007), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (#792532 and #860003), the European Commission (SUPPORT-E, #101015756) and by PPOC (#20_21 L2506), the NHMRC Leadership Investigator Grant (#1173871).
•An overview of current knowledge on anaesthesia and neuromuscular disorders was presented.•A multidisciplinary approach is essential for optimal peri-operative care for patients with neuromuscular ...disorders.•New developments in the field of malignant hyperthermia were discussed.•Experts in the field of anaesthesia, genetics and neuromuscular disorders committed to work on ENMC consensus statements concerning the anaesthetic management of patients with neuromuscular disorders and genetic counselling in RYR1-related disorders.•International registries can be of great importance for future research in the field of anaesthesia and neuromuscular disorders.
The rat is the most extensively studied model organism and is broadly used in biomedical research. Current rat disease models are selected from existing strains and their number is thereby limited by ...the degree of naturally occurring variation or spontaneous mutations. We have used ENU mutagenesis to increase genetic variation in laboratory rats and identified a recessive mutant, named tornado, showing aberrant circling behavior, hyperactivity, and stereotypic head shaking. More detailed analysis revealed profound deafness due to disorganization and degeneration of the organ of Corti that already manifests at the onset of hearing. We set up a single nucleotide polymorphism (SNP)-based mapping strategy to identify the affected gene, revealing strong linkage to the central region of chromosome 1. Candidate gene resequencing identified a point mutation that introduces a premature stopcodon in Myo7a. Mutations in human MYO7A result in Usher syndrome type 1B, a severe autosomal inherited recessive disease that involves deafness and vestibular dysfunction. Here, we present the first characterized rat model for this disease. In addition, we demonstrate proof of principle for the generation and cloning of human disease models in rat using ENU mutagenesis, providing good perspectives for systematic phenotypic screens in the rat.
Caffeine is the most widely consumed psychoactive substance in the world. Strikingly, the molecular pathways engaged by its regular consumption remain unclear. We herein addressed the mechanisms ...associated with habitual (chronic) caffeine consumption in the mouse hippocampus using untargeted orthogonal omics techniques. Our results revealed that chronic caffeine exerts concerted pleiotropic effects in the hippocampus at the epigenomic, proteomic, and metabolomic levels. Caffeine lowered metabolism-related processes (e.g., at the level of metabolomics and gene expression) in bulk tissue, while it induced neuron-specific epigenetic changes at synaptic transmission/plasticity-related genes and increased experience-driven transcriptional activity. Altogether, these findings suggest that regular caffeine intake improves the signal-to-noise ratio during information encoding, in part through fine-tuning of metabolic genes, while boosting the salience of information processing during learning in neuronal circuits.
A measurement of vector analyzing powers in elastic deuteron-carbon scattering has been performed at the Cooler Synchrotron COSY of Forschungszentrum Jülich, Germany. Seven kinetic beam energies ...between 170 and 380 MeV have been used. A vector-polarized beam from a polarized deuteron source was injected, accelerated to the final desired energy and stored in COSY. A thin needle-shaped diamond strip was used as a carbon target, onto which the beam was slowly steered. Elastically scattered deuterons were identified in the forward direction using various layers of scintillators and straw tubes. Where data exist in the literature (at 200 and 270 MeV), excellent agreement of the angular shape was found. The beam polarization of the presented data was deduced by fitting the absolute scale of the analyzing power to these references. Our results extend the world data set and are necessary for polarimetry of future electric dipole moment searches at storage rings. They will as well serve as an input for theoretical description of polarized hadron-hadron scattering.
The Amaldi 10 Parallel Session C3 on Advanced Gravitational Wave detectors gave an overview of the status and several specific challenges and solutions relevant to the instruments planned for a ...mid-decade start of observation. Invited overview talks for the Virgo, LIGO, and KAGRA instruments were complemented by more detailed discussions in presentations and posters of some instrument features and designs.
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